______ _______ ______ _______ Genetic Diseases

Basic Punnett Square In this scenario, both parents are heterozygous for a particular allele A = dominant allele a=recessive allele If these two individuals were to produce offspring, the possibility of their child having a certain genotype is as such: AA, homozygous dominant 1:4 Aa, heterozygous 1:2 Aa, homozygous recessive 1:4

If the disease we were concerned about was expressed through a dominant allele, the offspring would have a 3:4 chance of inheriting the disease. affected unaffected

affected If the disease we were concerned about was expressed through a recessive allele, the offspring would have a 1:4 chance of inheriting the disease. Aa offspring are “carriers”. Although they may not express the phenotype associated with a recessive disease, they carry an allele for it, and thus can pass it on to their offspring.

Why do alleles cause these disorders? Mutations arise in genes that are passed down to through the alleles to the offspring.

Tay Sachs Disease  An autosomal recessive disorder  Causes a buildup of gangliosides in the brain, resulting in mental retardation and eventually death  Caused by a mutation of the HEXA gene on chromosome 15  Time of onset of disease is crucial  If onset is during infancy, disease is severe and mortality is high  If onset is during juvenile or adult years, mortality not as high

Infantile-onset Neurological deterioration between 3- 6 months of age Motor development plateaus/regresses at months Loss of vision begins at 1 year of age (cherry red spot starts) Seizures begin at end of age 1 Loss of voluntary movement by age 2 Death by 2-4 years Adult-onset Manifests at 2-4 years of age Begins with neurological deterioration By age 10, individuals with juvenile Tay Sachs will experience seizures By years of age, most individuals will enter a vegetative state Juvenile-onset Great variability in clinical symptoms Less than half of individuals with adult Tay Sachs have psychiatric manifestations Vision is rarely affected The Difference in Years

The Cherry Red Spot Individuals with Tay Sachs disease are often identified by the “cherry red spot” seen when they receive an eye examination. The red circle seen towards the center of the eye is actually normal retina, while the white surrounding cells are the ones affected by abnormal storage of gangliosides in the retinal neurons.

Achondroplasia (Dwarfism) Achondroplasia is the most common cause of dwarfism in humans Autosomal dominant disorder Mutations that are linked to growth factors are the primary causes of dwarfism In the case of achondroplasia, the mutation lies in FGFR3 – “gain of function” mutation : FGFR3 becomes overactive Affects all races

Radiographs of two fetus at 34 weeks. The two pictures on the left are from a normal fetus, and the two on the right from a fetus with achondroplasia.

Achondroplasia is a Dominant Disorder Dominantly inherited traits are easily identified on a pedigree because they are expressed every generation. I II III IV

Sickle Cell Anemia An autosomal recessive disorder The sickle cell allele is known as Hs. When oxygen content is low, the diseased hemoglobin deforms into a sickle shape. The constant change between normal oxygenated red blood cells and deoxygenated sickle cells causes some cells to become permanently sickled. It is most common individuals of African-American descent

The mutation is caused by the substitution of a single amino acid in HBB.

Symptoms of sickle cell anemia Anemia Failure to thrive Repeated infections Dactylitis (painful swelling of hands and feet) Stroke Leg ulcers (shown on the left) Visual loss Bone aseptic necrosis Splenomegaly

The sickle cell allele provides unique traits that benefits its carriers Although Sickle Cell Anemia is overall a recessive disorder, the alleles express incomplete dominance at the molecular level. Those who are carriers of the disease express certain traits sickle cell anemia. Their cells do produce some fibrous polymers, but not enough to cause harm to the individual. The majority of carriers express no symptoms of sickle cell and are overall clinically silent. Individuals heterozygous for sickle cell are also resistant to malaria. This is a survival advantage in areas where malaria is a major concern, and has helped the disorder prevail.

Geographic overlap of sickle cell anemia with malaria is most evident in Africa

Amniocentesis A small amount of fetal tissue is taken from the placenta via spinal needle or cannula. Ultrasound is used in conjunction with this test to ensure the safety of the fetus. Results are obtained within 24 hours of the procedure because the cells obtained from the placenta divide at a rapid rate. This test may be performed 8-10 weeks after conception. Chorionic Villus Sampling ml of amniotic fluid is taken from the amniotic cavity with a needle for various tests. Ultrasound is usually used during the procedure to ensure the safety of the fetus. This procedure can be performed at weeks after conception, and takes several weeks to complete.

Ultrasound Sound waves are used to produce the image of the fetus. Fetoscopy A tube containing fiber optics and a viewing scope is inserted into the uterus to view the fetus for anatomical abnormalities and/or deformities.